Thread by @Ayjchan

In anticipation of some excellent articles on the origins of covid-19 coming out next week, I think it would be useful to cover a few areas of confusion relating to what experts mean by the "origins" of a virus, what counts as lab origins, and what counts as Gain-of-Function.

Over the past months, we've seen reports of SARS2-like viruses discovered across a wide geographic area from Thailand to Japan. Still the closest relatives to SARS2 are viruses from Yunnan, China.

What does this tell us about the origins of SARS2 and how it emerged in Wuhan?

Frankly, it tells us what we've known since the beginning.

That the ancestral origins of SARS2, like other SARS viruses, is in 🦇 and that the hotspot is in Yunnan, China or proximal to Yunnan.

Some experts are very keen to sample SE Asia just across the border from Yunnan...

Scientists are keen to sample viruses in those caves in Yunnan, China where the closest relatives of SARS2 were discovered, one (RaTG13) as early as 2013. WIV also revealed in Nov 2020 they had 8 other SARS virus from this mine.

But these lorries...
bbc.com/news/world-asi…

Access to these caves is extremely restricted: "A bat research team visiting recently managed to take samples but had them confiscated, two people familiar with the matter said. Specialists in coronaviruses have been ordered not to speak to the press."
apnews.com/article/united…

So, if you're looking for the ancestral bat origins of SARS2, some would say we have ALREADY found it. It's in Yunnan, China - similar to the ancestral bat origins of SARS1.

You've got super close matches to SARS2 from these caves, just missing that S1/S2 FCS insertion.

People shouldn't be surprised to hear that more and more SARS2-like viruses in bats (big green circle) are being found in the wild. Especially in the well-known spillover zone in South China and some of SE Asia.

Where do you think labs are getting these viruses from? Comets?😅

But when many people think about finding the origins of the virus, they're not thinking about the ancestral bat origins.

They're thinking about how did SARS2 get from those bats into Wuhan?

Did the virus pass from bats or an intermediate host or through a lab to humans?

In that sense, the origins of covid-19 that most people are looking for are not the ancestral bat reservoir of SARS2 (big green circle).

People are trying to figure out the origins scenario - was it A. natural spillover, B-E. lab leak, or even F. #PopsicleOrigins

One major major misconception among non-scientists and even some scientists, surprisingly, is that lab origins = some magical situation where scientists have created or designed a virus unlike any we've sampled from nature (see magical rainbow circle).

Some scientists only see the rainbow circle as lab origins. In this scenario, any natural virus similar to SARS2 would be inconsistent with "lab magic" origins.

They maybe haven't considered lab-based scenarios B-E, which are consistent with natural SARS2-like viruses existing.

To those scientists, I'd like to make it super clear that when many people are discussing lab origins, they're talking about plausible scenarios B-E. There are precedents of SARS1 leaking from labs. In one situation resulting in a quarantine of more than 1000 people.

I know no one who is seriously suggesting the "lab magic" scenario.

If SARS2 leaked from a lab, it must be based on a natural virus that was sampled from nature.

This brings us to the question of what counts as Gain of Function (GOF) research within scenarios B-E.

And whether this terminology even matters in the search for the origins of covid-19.

At the least exclusive end of "what is GOF?" you could consider even scenario C as possible GOF.

If you passage viruses in cell or animal models, it will pick up mutations, even if it wasn't your intention. Some scientists consider this falling under GOF.

At the most exclusive end of "what is GOF?" some scientists insist that there must be a clear gain of function (regardless of intent) - a clear, anticipated, probable increase in transmissibility or pathogenicity of the pathogen you're modifying, whether by scenario C, D, or E.

It's safe to say this GOFRoC debate is radioactive and scientists will "I told you so" each other to death even at the risk of overshadowing the actual problem of preventing a future lab-based pandemic that could result from non-GOF work (spanning B-E).

https://twitter.com/Ayjchan/status/1370881949619851271

When I watched this video from May 2020, I was worried that top scientists had not given much thought to the idea of lab/research activities contributing to the emergence of novel pathogens/pandemics.

Research does not need to be GOF to constitute a risk.

https://twitter.com/NatGeoMag/status/1257715740364492801

Specifically, at ~1:20min in the interview, Dr Fauci asks does it matter if a natural virus leaked from a lab and caused a pandemic (scenarios B and C).

I'd say yes. It seriously matters.

Because it changes the pandemic mitigation strategy entirely.

The question is essentially, does it matter that we're sending dozens of personnel into remote, difficult to access natural habitats (e.g. bat caves) & villages to sample 10,000s of animals & humans, & bring those personnel & samples back into densely populated cities for study?

Whether GOF research is occurring is another layer on top of that.

If bad actors or even well-intentioned actors are tinkering with the hundreds or thousands of pathogen sequences in their collection to understand how pathogens work... and if this is a risk to humanity.

I don't have a constructive answer for this situation where some nations are investing in prolific virus hunting & GOF research.

But we should convene a wide range of international experts to talk about it at a public forum.

Even accidental pandemics have a colossal impact.

FYI some people have been asking me to organize such a forum or investigation.

I think you're seriously mistaken about what a scientific trainee has the powers to do. I think even a full professor would have difficulties arranging such an event.

"Erm, hi, would you maybe like to attend and possibly even speak at a conference where you and the vast majority of our peer reviewers and grant reviewers are criticized for underestimating the risks associated with pathogen research?"

Let's ask a postdoc to organize this event.

People, I can't even get a manuscript on the origins of SARS-CoV-2 / covid-19 past (reputable) peer review.

You're seriously overestimating my powers.

I repositioned the impossible "Lab Magic" scenario and gave it its own letter 'G' because people pointed out that it was getting confused with scenario E, which is possible and supported by scientific literature showing the WIV has been building chimeric SARS viruses for years.